Nuclear factor-kappaB (NF-kappaB) plays a key role in the expression of many genes central to the rheumatic diseases. Participation of this transcription factor in the expression of IL-1b in monocytes, and ICAM-l, TNF-alpha and IL-6 in rheumatoid synoviocytes has been demonstrated. Also, the transcription factor regulates inducible expression of the cell adhesion molecules Eselectin, VCAM-l and ICAM-l in vascular endothelial cells. A primary goal of my laboratory is to develop intra-articular gene therapy for rheumatoid arthritis using a dominant negative adenoviral IkappaB kinase (DN IKK2) construct to block NF-kappaB activation. In vitro studies demonstrated that IKK2 is the primary pathway that regulates synoviocyte production of cytokines like IL-6 and IL-8. In vivo studies have shown that suppression of IKK2 using intra-articular DN IKK2 inhibits clinical arthritis in the adjuvant arthritis model in rats. In preparation for human studies with DN IKK2, we propose to determine the distribution and duration of expression of IKK2 construct in joints after direct intra- articular gene therapy. We will then evaluate the toxicology of the adenoviral construct in rats.